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US7964218B2 - Granular preparations for oral administration - Google Patents

Granular preparations for oral administration Download PDF

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Publication number
US7964218B2
US7964218B2 US10/363,680 US36368003A US7964218B2 US 7964218 B2 US7964218 B2 US 7964218B2 US 36368003 A US36368003 A US 36368003A US 7964218 B2 US7964218 B2 US 7964218B2
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United States
Prior art keywords
grain
coating
weight
plain
oral
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Expired - Fee Related, expires
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US10/363,680
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English (en)
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US20040101567A1 (en
Inventor
Tatsuo Nomura
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Mitsubishi Tanabe Pharma Corp
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Mitsubishi Tanabe Pharma Corp
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Assigned to MITSUBISHI PHARMA CORPORATION reassignment MITSUBISHI PHARMA CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NOMURA, TATSUO
Publication of US20040101567A1 publication Critical patent/US20040101567A1/en
Assigned to MITSUBISHI TANABE PHARMA CORPORATION reassignment MITSUBISHI TANABE PHARMA CORPORATION CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: MITSUBISHI PHARMA CORPORATION
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38Cellulose; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/74Synthetic polymeric materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/74Synthetic polymeric materials
    • A61K31/785Polymers containing nitrogen
    • A61K31/787Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5036Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5036Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to an oral grain preparation. More specifically, the invention relates to an oral grain preparation having excellent property for easy taking.
  • Dry syrups suspended in situ before administration, have conventionally been commercially available for anion exchange resin preparations which need a large dose.
  • the dry syrups are inconvenient, because they take time for administration and require a large single dose.
  • Some tablets have also been studied, however, no research has been made as for a relation between a size or a coating formulation of tablets and a property for easy take. Accordingly, a preparation that achieves higher compliance has been desired.
  • a tablet containing an anion exchange resin as a major component is required not to disintegrate in the mouth, but to rapidly disintegrate in the body so as to exhibit its efficacy.
  • No published book describes what degree of non-disintegration in the mouth is sufficient.
  • practical sensory tests were employed by placing agents in the mouth for about 20 seconds and then spitting out the agents for evaluation with the purpose of prevention of the taste for 20 to 30 seconds.
  • an oral grain preparation with an excellent property for easy taking which comprises anion exchange resins as active components, can be obtained by coating plain grains having a diameter of 3 to 4 mm with a solution of a water-soluble cellulose polymer, and further coating with an aqueous dispersion of ethyl cellulose.
  • FIG. 1 depicts a relation between the amount of coating in a coated tablet (percent by weight based on the weight of a plain grain) and disintegration starting time (sec.).
  • the gist of the present invention is an oral grain preparation comprising an anion exchange resin as an active ingredient, which is obtained by coating plain grains having a diameter of 3 to 4 mm with 2 to 8% by weight of water-soluble polymer cellulose solution and 0.5 to 4% by weight of ethyl cellulose aqueous dispersion (for example, trade name “AQUACOAT”; an aqueous dispersion of ethylcellulose, cetanol and sodium lauryl distributed by FMC Biopolymer, also available from Asahi Kasei Corporation and Shin-Etsu Chemical Co., Ltd), wherein the total coating amount is 6 to 8.5% by weight (hereinafter the coating amount will be indicated by “% by weight” based on the weight of the plain grain).
  • an anion exchange resin as an active ingredient
  • a large dosage is required for an anion exchange resin, and if the diameter of grains is as small as 3 to 4 mm, the number of grains for one dosage become as much as about 50 to 100.
  • a water-soluble cellulose polymer solution is solely used for coating, adherence of each grains in the mouth will occur due to the peculiar sliminess.
  • 30 to 50% of powdered ethyl cellulose or low-substituted hydroxypropylcellulose is often added before coating to the water-soluble cellulose polymer solution as a coating base material.
  • a grain preparation that is coated with 3% by weight of a water-soluble cellulose polymer solution and 4 or 5% of an ethylcellulose aqueous dispersion will generate small cracks on the film which contains a large amount of water-insoluble components, which results in a lowering of film strength.
  • anion exchange resins have sand-like taste, and disintegration of a preparation in the mouth will remarkably deteriorate a feeling of taking.
  • high moisture adsorption will swell the preparation, which will cause adhesion to the mucosa in the mouth and difficulty in swallow due to the significant swell in the mouth. Therefore, it is required that no disintegration occurs in the mouth at the time of taking.
  • disintegration time of a grain preparation can be delayed and controlled by a coating with a water-soluble cellulose polymer solution and an ethylcellulose aqueous dispersion in combination.
  • an oral cholesterol-lowering agent thus obtained is free from an unpleasant feeling at taking such as caused by a large tablet, and the agent needs a smaller dosage than that of granules, attributable to a high density, and gives good feeling of taking.
  • the gist of the present invention also exists in a method for manufacture of an oral grain preparation, which comprises the following steps:
  • Step 1 14 to 20% by weight of water is added and mixed to an anion exchange resin, and then 2% by weight or less of silicon dioxide based on the weight of the anion exchange resin is mixed. After the mixture is recovered, a lubricant is added and the resultant is subjected to tablet compression to obtain a plain grain with a diameter of 3 to 4 mm.
  • Step 2 The plain grain is coated with 2 to 8% by weight of a water-soluble cellulose polymer solution and then with 0.5 to 4% by weight of an ethylcellulose aqueous dispersion (30% by weight of a solid content).
  • examples of the agents that swell in the mouth, used as an active ingredient include anion exchange resins.
  • the anion exchange resins are not particularly limited.
  • a particularly preferred example includes 2-methylimidazole-epichlorohydrin copolymer (hereinafter referred to as “MCI-196”) obtained by the method described in Japanese Patent Unexamined Publication (KOKAI) No. (Sho) 60-209523.
  • Plain grains having a diameter of 3 to 4 mm are prepared by using the active ingredient.
  • the plain grains may be pills and the like, or compressed preparations such as tablets.
  • a lubricant such as hydrogenated oil and mixed
  • the thus prepared plain grains comprising the anion exchange resin are coated with a coating solution containing water-soluble cellulose polymer such as hydroxypropylmethylcellulose by using a coating machine such as High Coater HCT-30 (Freund Industrial Co., Ltd.) under the conditions of, for example, a suction temperature of 80 to 90° C. and a spraying speed of 5 to 10 g/min.
  • a coating machine such as High Coater HCT-30 (Freund Industrial Co., Ltd.) under the conditions of, for example, a suction temperature of 80 to 90° C. and a spraying speed of 5 to 10 g/min.
  • plain grains with a smaller diameter are coated by a coating machine provided with a punching device for granules.
  • Any water-soluble cellulose polymers may be used as long as they are cellulose polymers that are water-soluble. Hydroxypropylmethylcellulose, hydroxypropylcellulose, and methylcellulose are preferred, and hydroxypropylmethylcellulose is particularly preferred.
  • ethylcellulose aqueous dispersions may be used as long as they are aqueous dispersions containing ethylcellulose.
  • An aqueous dispersion of a latex-type aqueous coating agent containing ethylcellulose as a base material is preferred.
  • An example includes AQUACOAT (trade name, obtained from Asahi Kasei Corporation).
  • a coating amount of the water-soluble cellulose polymer (hereinafter referred to as “undercoating”) is 2 to 8% by weight, and most preferably 4 to 6% by weight. Further, a coating amount of the ethylcellulose aqueous dispersion (hereinafter referred to as “overcoating”) is 0.5 to 4% by weight, more preferably 1 to 2% by weigh of, for example, AQUACOAT (trade name, obtained from Shin-Etsu Chemical Co., Ltd.) to carry out the coating.
  • the oral grain preparations of the present invention have a diameter of 3 to 4 mm, and are free from sliminess peculiar to cellulose. Further, the preparations cause no adherence of each grains in the mouth after taking, and they have excellent feeling of taking without unpleasant feeling caused by large tablets.
  • a dosage of the oral grain preparation of the present invention is 1 to 10 g, preferably 1.5 to 4 g per day for adult, which may be taken once to three times a day as divided doses before or after meals, or between meals.
  • the oral grain preparation of the invention may be obtained by coating a plain grain comprising an anion exchange resin having a diameter of 3 to 4 mm with a solution of the water-soluble cellulose polymer at an amount of 3.5 to 8% by weight and then coating the plain grain with an aqueous dispersion of ethylcellulose at an amount of 0.5 to 4% by weight, wherein the total coating amount is 5.5 to 8.5% by weight based on the weight of the plain grain.
  • the oral grain preparation of the invention may be obtained by coating a plain grain with the solution of the water-soluble cellulose polymer at an amount of 3.5 to 8% by weight and then coating the plain grain with the aqueous dispersion of ethylcellulose at an amount of 0.5 to 4% by weight, wherein the total coating amount is 5.5 to 8.5% by weight based on the weight of the plain grain.
  • the oral grain preparation of the invention may be obtained by coating a plain grain comprising an anion exchange resin having a diameter of 3 to 4 mm with a solution of the water-soluble cellulose polymer at an amount of 4 to 6% by weight and then coating the plain grain with an aqueous dispersion of ethylcellulose at an amount of 1 to 2% by weight, wherein the total coating amount is 6 to 8% by weight based on the weight of the plain grain.
  • the oral grain preparation of the invention may be obtained by coating a plain grain with the solution of the water-soluble cellulose polymer at an amount of 4 to 6% by weight and then coating the plain grain with the aqueous dispersion of ethylcellulose at an amount of 1 to 2% by weight, wherein the total coating amount is 6 to 8% by weight based on the weight of the plain grain.
  • the resulting plain grains were subjected to coating using a High Coater HCT-30 under the conditions of 80° C. suction temperature and 5 g/min spraying speed.
  • the coating was carried out in two steps.
  • the first coating solution whose composition is shown as Formulation 1, was prepared by dissolving hydroxypropylmethylcellulose in water, adding titanium oxide, talc, and polyethylene glycol and well mixing the mixture, and passing the mixture through a sieve of 80 mesh to use for the coating.
  • the coating amount was 4.25% by weight based on the weight of the plain grains.
  • the coating was successively carried out with a coating solution of the composition described as Formulation 2.
  • the coating amount was 2.17% by weight based on the weight of the plain grains.
  • 0.12 g of hydrogenated oil was added and polishing was performed.
  • Formulation 1 Composition of the undercoating solution Hydroxypropylmethylcellulose 4.0% by weight Titanium oxide 0.5 Talc 0.5 Polyethylene glycol 0.8 Purified water 94.2 Total 100.0% by weight
  • Formulation 2 Composition of the overcoating solution Ethylcellulose aqueous dispersion 50.0% by weight (trade name: AQUACOAT, 30% solid content) Triacetin 4.5 Purified water 45.5 Total 100.0% by weight
  • Plain grains were prepared in the same manner as in Example 1 and the coating solutions had the same compositions, except the amounts of undercoating and overcoating were changed (each % by weight).
  • Undercoating amount Overcoating amount 4% 2 and 3% 5% 1, 2, and 3%
  • Plain grains were prepared in the same manner as in Example 1 and the coating solutions had the same compositions, except the amounts of undercoating and overcoating were changed (each % by weight).
  • Undercoating amount 3% 0, 1, 2, and 3% 4% 0 and 1% 5% 0%
  • Example 2 plain grains having the diameter of 4.5 mm were prepared.
  • the composition of each coating solution and each coating amount were the same as those in Example 1.
  • Plain grains were prepared in the same manner as in Example 1. Water-soluble polymer cellulose and ethylcellulose aqueous dispersion were mixed, and according to the composition shown in Formulation 3, 7% by weight of coating was applied to the plain grains.
  • Composition 3 Hydroxypropylmethylcellulose 4.0% by weight Titanium oxide 0.5 Talc 0.5 Ethylcellulose aqueous dispersion 0.0% by weight (trade name: AQUACOAT, 30% solid content) Triacetin 4.5 Purified water 40.5 Total 100.0% by weight
  • Example 2 For preparations of Example 2 and Comparative Example 1, starting times of disintegration of each preparations in water were compared. It can be understood that the starting time of disintegration of the preparation in water was remarkably delayed by the undercoating and successive small amount of overcoating according to the present invention.
  • the starting time of disintegration of each preparations shown in FIG. 1 was determined by placing 50 ml of purified water at 37° C. into a 100 ml beaker, adding 6 pieces of the preparation and measuring a time before the break of the coating film. Average values are indicated.
  • the sensory evaluations were performed by employing eight test subjects, each received 2 g dosage (3 tablets only for the 500 mg tablet), for the following items.
  • the plain grains were coated at approximately 2.7% by weight using the undercoating formulation (Formulation 1).
  • Three grades were assigned for the sensory evaluation, and as described below, higher scores were given in gradient manner to preferred results.
  • Total scores for each item of the evaluation are summarized in Table 2.
  • Appearance visible appearance; easy for taking (3), slightly difficult for taking (2), and difficult for taking (1)
  • the diameter and sliminess of each grain preparation and the tablet had significant effect on the feeling for taking.
  • the evaluation revealed that the diameter of 3 mm was sufficient for easy taking, whilst the diameter of 4.5 mm gave difficulty in taking.
  • the water-soluble polymer cellulose and the ethylcellulose aqueous dispersion were mixed and subjected to coating of the tablets, sliminess was not eliminated, which indicates necessity of the double coating for elimination of sliminess.
  • the sliminess was eliminated when the overcoating amount was 1% or more by weight.
  • an oral grain preparation by applying an inner coating layer of a water-soluble cellulose polymer and an outer coating of ethylcellulose on a plain grain, comprising an anion exchange resin as an active ingredient and having a diameter of 3 to 4 mm, an oral grain preparation can be provided which is free from sliminess, which is peculiar to cellulose, and adherence of each grains in the mouth at taking, and has excellent feeling for taking without an unpleasant feeling such as caused by a large tablet.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US10/363,680 2000-09-06 2001-09-05 Granular preparations for oral administration Expired - Fee Related US7964218B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2000269526 2000-09-06
JP2000-269526 2000-09-06
PCT/JP2001/007697 WO2002019993A1 (fr) 2000-09-06 2001-09-05 Preparations de granules pour administration orale

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US20040101567A1 US20040101567A1 (en) 2004-05-27
US7964218B2 true US7964218B2 (en) 2011-06-21

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US (1) US7964218B2 (de)
EP (1) EP1323418B1 (de)
JP (1) JP3883505B2 (de)
KR (1) KR100790056B1 (de)
CN (1) CN1250205C (de)
AT (1) ATE476968T1 (de)
AU (1) AU2001284434A1 (de)
CA (1) CA2421240C (de)
DE (1) DE60142789D1 (de)
ES (1) ES2350307T3 (de)
WO (1) WO2002019993A1 (de)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR112012024683B1 (pt) 2010-03-31 2019-09-24 Mochida Pharmaceutical Co., Ltd. Composição oral
CN103813807B (zh) 2011-09-30 2017-02-08 持田制药株式会社 易服用性固体制剂
CN105476969A (zh) * 2015-12-18 2016-04-13 北京万全德众医药生物技术有限公司 考来替兰分散片及其制备方法

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2009736A1 (en) 1989-02-11 1990-08-11 Manfred Bucheler Medicaments having controlled release of the active compound
US4999189A (en) * 1988-11-14 1991-03-12 Schering Corporation Sustained release oral suspensions
CA2040471A1 (en) 1990-04-17 1991-10-18 Massimo Maria Calanchi Controlled release drug formulation
EP0637447A2 (de) 1993-08-03 1995-02-08 Mitsubishi Chemical Corporation Oral verabreichbares cholesterinsenkendes Mittel
WO1998015265A1 (en) 1996-10-04 1998-04-16 Danbiosyst Uk Limited Colonic delivery of weak acid drugs
EP0873129A1 (de) 1996-10-15 1998-10-28 Hisamitsu Pharmaceutical Co. Inc. Anionenaustauscherharze enthaltende tabletten
US6066336A (en) * 1997-09-29 2000-05-23 Bristol-Myers Squibb Company Cholesterol-lowering tablets
US6171618B1 (en) * 1996-05-29 2001-01-09 Pfizer Inc. Combination dosage form comprising cetirizine and pseudoephedrine
US6174873B1 (en) * 1998-11-04 2001-01-16 Supergen, Inc. Oral administration of adenosine analogs

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4999189A (en) * 1988-11-14 1991-03-12 Schering Corporation Sustained release oral suspensions
CA2009736A1 (en) 1989-02-11 1990-08-11 Manfred Bucheler Medicaments having controlled release of the active compound
CA2040471A1 (en) 1990-04-17 1991-10-18 Massimo Maria Calanchi Controlled release drug formulation
EP0637447A2 (de) 1993-08-03 1995-02-08 Mitsubishi Chemical Corporation Oral verabreichbares cholesterinsenkendes Mittel
US5447726A (en) * 1993-08-03 1995-09-05 Mitsubishi Kasei Corporation Orally administrable cholesterol lowering agent
US6171618B1 (en) * 1996-05-29 2001-01-09 Pfizer Inc. Combination dosage form comprising cetirizine and pseudoephedrine
WO1998015265A1 (en) 1996-10-04 1998-04-16 Danbiosyst Uk Limited Colonic delivery of weak acid drugs
EP0873129A1 (de) 1996-10-15 1998-10-28 Hisamitsu Pharmaceutical Co. Inc. Anionenaustauscherharze enthaltende tabletten
US6066336A (en) * 1997-09-29 2000-05-23 Bristol-Myers Squibb Company Cholesterol-lowering tablets
US6174873B1 (en) * 1998-11-04 2001-01-16 Supergen, Inc. Oral administration of adenosine analogs

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
"Grain". Dictionary.com. Jan. 2005. Online. Internet. Accessed on Jan. 25, 2006. . *
"Grain". Dictionary.com. Jan. 2005. Online. Internet. Accessed on Jan. 25, 2006. <http://dictionary.reference.com/search?q=grain>. *
Canadian Intellectual Property Office Search Report issued Oct. 22, 2008 in Canadian Application No. 2,421,240 of which the present application corresponds.
Dow ETHOCEL premium polymers for pharmaceutical applications: product data sheet (Oct. 1998). *
European Office Action issued Aug. 6, 2008 corresponding to European application 01 963 438.5.
Mesh size conversion table (Wikipedia). *
Official Action issued on Sep. 10, 2004 in the corresponding Chinese application, together with English translation thereof.
Safety MSDS data for diethylaminoethanol. Accessed online on Aug. 28, 2008 at http://msds.chem.ox.ac.uk/DI/diethylaminoethanol.html. pp. 1-2. *
Z. G. Yang, "Preparation of Pulsatile Controlled-Release Pellets of Theophylline", Pharma. J. Chin. PLA, vol. 16, No. 1, Feb. 2000, with English abstract.

Also Published As

Publication number Publication date
EP1323418A4 (de) 2007-05-30
KR100790056B1 (ko) 2007-12-31
CA2421240C (en) 2010-03-23
ATE476968T1 (de) 2010-08-15
WO2002019993A1 (fr) 2002-03-14
JP3883505B2 (ja) 2007-02-21
EP1323418A1 (de) 2003-07-02
JPWO2002019993A1 (ja) 2004-01-15
CN1452480A (zh) 2003-10-29
ES2350307T3 (es) 2011-01-20
US20040101567A1 (en) 2004-05-27
DE60142789D1 (de) 2010-09-23
AU2001284434A1 (en) 2002-03-22
EP1323418B1 (de) 2010-08-11
CA2421240A1 (en) 2003-03-05
KR20030036756A (ko) 2003-05-09
CN1250205C (zh) 2006-04-12
WO2002019993A8 (fr) 2003-11-13

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